Virginia Andreoli

GABA(B) receptor 1 polymorphism (G1465A) is associated with temporal lobe epilepsy

Background: Dysfunction of γ-aminobutyric acid (GABA) (B) receptors has been implicated in the pathogenesis of temporal lobe epilepsy (TLE). Objective: To evaluate the genetic contribution of cloned human GABA(B) receptors to TLE. Methods: The authors genotyped 141 patients (78 women and 63 men; mean age = 49.1 ± 18.0 years) with nonlesional TLE and 372 age- and sex-matched normal individuals for the known polymorphism G1465A in the human GABA(B) receptor 1 [GABA(B[1])] gene. Results: There was a highly significant overrepresentation of the G1465A heterozygote in patients with TLE compared with controls. The A/G genotype was found in 17% of the 141 patients with TLE and in only 0.5% of the 372 controls (p < 0.0001). The authors also found that patients carrying the A allele had a significantly higher risk (p = 0.003, OR = 6.47, 95% CI = 2.02 to 20.76) of developing drug-resistant TLE. Furthermore, the age at onset of seizures tended to be lower in patients with A/G genotype, but the difference was not significant. Conclusions: The results of this study indicate that the GABA(B[1]) polymorphism (G1465A) confers a highly increased susceptibility to TLE. Moreover, it seems to influence the severity of this common epileptic disorder.

Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis

Abstract.Background:Cognitive impairment may occur at any time during the course of multiple sclerosis (MS), and it is often a major cause of disability in patients with the disease. The APOE-ε4 allele is the major known genetic risk factor for late onset familial and sporadic Alzheimer’s Disease (AD), and it seems to be implicated in cognitive decline in normal elderly persons.Objective:To investigate the clinical and genetic variables that can be associated with the cognitive decline in patients with MS.Methods:Five-hundred and three patients with clinically definite MS underwent a battery of neuropsychological tests and, according to the number of failed tests, were divided into cognitively normal and impaired. All patients were genotyped for APOE gene polymorphisms.Results:Fifty-six percent of MS patients showed, to different extents, cognitive impairment. Cognitive decline was predominant in men and was associated with disease duration, Kurtzke Expanded Disability Status Scale (EDSS) score, a low level of education, and, interestingly, the ε4 allele of the APOE gene. By contrast, cognitive impairment in women was independent of any investigated variable.Conclusion:The findings demonstrate that clinical and genetic factors play a role in men affected by MS developing cognitive impairment.

Dopamine D2 receptor gene polymorphism and the risk of levodopa-induced dyskinesias in PD.

OBJECTIVE To investigate whether polymorphisms in the genes for dopamine receptors D1 and D2 are associated with the risk of developing peak-dose dyskinesias in PD. BACKGROUND Peak-dose dyskinesias are the most common side effects of levodopa therapy for PD. The identified predictors may only partially account for the risk of developing peak-dose dyskinesias because a substantial proportion of patients never develop peak-dose dyskinesias. Genetic factors could play a role in determining the occurrence of peak-dose dyskinesias. METHODS A case-control study of 136 subjects with sporadic PD and 224 population control subjects. We studied three polymorphisms involving the dopamine receptor D1 gene and one intronic short tandem repeat polymorphism of the dopamine receptor D2 gene. RESULTS The polymorphisms of the dopamine receptor D1 gene were not associated with the risk of developing PD or peak-dose dyskinesias. The 15 allele of the polymorphism of the dopamine receptor D2 gene was more frequent in parkinsonian subjects than in control subjects. More important, the frequency of both the 13 allele and the 14 allele of the dopamine receptor D2 gene polymorphism was higher in nondyskinetic than in the dyskinetic PD subjects. The risk reduction of developing peak-dose dyskinesias for PD subjects carrying at least 1 of the 13 or 14 alleles was 72% with respect to the PD subjects who did not carry these alleles. CONCLUSIONS Certain alleles of the short tandem repeat polymorphism of the dopamine receptor D2 gene reduce the risk of developing peak-dose dyskinesias and could contribute to varying susceptibility to develop peak-dose dyskinesias during levodopa therapy.

APOE and risk of cognitive impairment in multiple sclerosis

Objectives‐ The APOE gene polymorphism and the −491 A/T polymorphism in its regulatory region have been associated with an increased risk for developing Alzheimers disease. We examined these polymorphisms in multiple sclerosis (MS) patients, to determine if a genetic predisposition may explain the risk for developing cognitive decline in MS. Material and methods‐ Eighty‐nine relapsing‐remitting and secondary progressive MS patients underwent to a full neuropsychological battery as well as to determination of APOE and −491 A/T polymorphisms. Genetic analysis was also performed in 107 population controls. Results‐ The APOE polymorphism was not associated with the risk of cognitive impairment in MS patients. The AA genotype of the −491 A/T polymorphism in the APOE regulatory region was more frequent in cognitively impaired than in cognitively preserved MS subjects. Conclusion‐ The AA homozygous state of the −491 AIT polymorphism of the APOE regulatory region is associated with cognitive impairment in patients with MS.

Apolipoprotein E genotype does not influence the progression of multiple sclerosis

Abstract.Objective:To investigate the association between apolipoprotein E (APOE) polymorphisms and the progression of MS.Methods:We investigated 428 subjects affected by clinically defined MS, with a disease duration of at least three years. We collected data concerning the age at onset of MS, clinical type, disease duration and disability according to the expanded disability status scale (EDSS). We also calculated the progression index (PI) to evaluate disease progression. APOE genotyping and the –491 A/T polymorphism of the APOE promoter were determined.Results:No association was observed between the APOE ε4 allele and clinical characteristics of our study population. We also investigated the –491 A/T APOE promoter polymorphism in 236 MS subjects and did not find any association between the –491 A/T polymorphism and the selected clinical variables.Conclusions:In our population the APOE ε4 allele and the –491 A/T APOE promoter polymorphism are not associated with a more rapid course of MS.

CD45 and multiple sclerosis: the exon 4 C77G polymorphism (additional studies and meta-analysis) and new markers

We re-evaluated the association with multiple sclerosis (MS) of the C77G splicing regulatory variation in the CD45 gene and screened for new mutations the three alternatively spliced exons (#4, 5 and 6). No association with C77G was detected in two groups of patients (total=448) and controls (total=559) from Northern and Southern Italy. When excluding the first published study indicating a positive association, a meta-analysis of the five further studies conducted to date (including the present one) led to a non-significant combined odds ratio (OR) of 1.11. None of the four newly identified nucleotide substitutions, namely C77T (Pro59Pro) in exon 4, G69C (Asp121His) in exon 5, T127A (Ile187Asn) and A138G (Thr191Ala) in exon 6, was significantly associated to MS.

Prodynorphin Gene Promoter Polymorphism and Temporal Lobe Epilepsy

∗†Antonio Gambardella, †Ida Manna, ∗†Angelo Labate, ‡Rosanna Chifari, †Paolo Serra, †Antonella La Russa, §Emilio LePiane, †Rita Cittadella, †Virginia Andreoli, §Francesco Sasanelli, ∗†Mario Zappia, §Umberto Aguglia, and ∗†Aldo Quattrone ∗Institute of Neurology, School of Medicine, Catanzaro; †Institute of Neurological Sciences, National Research Council, Cosenza; ‡Clinic of Neurology, Hospital of Melegnano, Milan; and §Regional Epilepsy Centre, Hospital of Reggio Calabria, Italy

Genetic association of α2-macroglobulin polymorphisms with AD in southern Italy

The authors investigated the segregation of two polymorphisms of the &agr;2-macroglobulin gene (A2M-I/D and A2M-Ile1000Val) in patients with sporadic AD from southern Italy. The A2M-I and A2M-Val1000 alleles were more frequent in cases than in controls, and this effect was independent from the APOE-&egr;4 status as well as from the age at onset of AD. Moreover, subjects carrying the A2M genotype I/I-Val/Val had a threefold increase of risk for AD. These data support a population-based susceptibility for AD linked to A2M polymorphisms.

A phenotypic variation of dominant optic atrophy and deafness (ADOAD) due to a novel OPA1 mutation.

Sirs: Autosomal Dominant Optic Atrophy (ADOA or Kier’s disease, OMIM #165500) is one of the most frequent forms of inherited optic atrophy [1], often presenting in the first decade of life with progressive impairment of visual acuity, variably combined with dyschromatopsia and optic nerve pallor [2]. More than 90 mutations spanning throughout the Optic Atrophy 1 (OPA1) gene were disease-associated with most cases of ADOA (http://lbbma.univ-angers.fr/ eOPA1/) [3]; the gene encodes a dynamin-related GTPase involved in mitochondrial biogenesis [4]. Genotype-phenotype comparisons have been inconclusive except for ADOA complicated with a rare sensorineural deafness (ADOAD); some authors reported that only the R445H mutation could be linked to ADOAD, as hearing loss has never been associated to other OPA1 mutations [5, 6]. Here we present a family with an unusual phenotype of ADOAD and peripheral polineuropathy associated with a novel OPA1 mutation. The proband (IV.13) (pedigree reported in Fig. 1) was a 38-year-old man from Southern Italy, who complained of bilateral and progressive reduction of visual acuity since the age of 7 years. In the second decade of his life, he experienced progressive deafness followed by development of an ataxic gait. At the time of the evaluation, he was legally blind (bilateral visual acuity less than 0.3) and almost deaf (loss of hearing more than 90 dB); on neurological examination he presented bilateral ophthalmoplegia, mild ataxia, distal weakness and severe reduction of proprioception. The auditory brainstem responses (ABRs) were suggestive of bilateral neurosensorial deafness; the electrodiagnostic study of his legs showed decreased amplitude of sensory potentials and motor responses which were consistent with a peripheral axonal neuropathy. Brain and spinal cord MRI were normal. Complete clinical, ophthalmological and audiological examinations were performed on the living family members (Fig. 1a). They were negative except for the proband’s daughter (V.14), a 6year-old child who was showing modest but progressive difficulties in visual acuity and hearing abilities during the last year. The ophthalmologic examination revealed mild bilateral optic pallor and the ABRs were bilaterally impaired (hearing loss < 40 dB); brain MRI and peripheral nerves electrophysiology were normal. After informed consent, genomic DNA was obtained from the proband and his relatives (the proband’s father, his daughter and wife, the 7 siblings and their spouses). The entire coding region and the intron-exon junctions of OPA1 were sequenced by ABIPRISM 3130xl Genetic Analyzer (Applied Biosystems – Foster City, CA), as described elsewhere [7]. A novel missense 1316 G > T mutation was found in exon 14 of the proband and his daughter (Fig. 1b–c). This base change causes the amino acid substitution of a highly conserved Glycine to Valine at codon 439 (G439V) in the GTPase domain of OPA1 gene. No other family members harbored the same DNA mutation. For confirmation, 100 gender, age and ethnicity matched chromosomes controls were analyzed with the same procedure; no one carried the novel OPA1 mutation. OPA1 is believed to play a key role in mitochondrial morphology and function, by promoting its fusion (with the interaction of Mitofusin-1,2) and regulating mitochondrial apoptosis. Frezza et al. [8] demonstrated that oligomerization of OPA1 regulates mitochondrial apoptosis by maintaining the tightness of cristae junctions. Experimental data suggested that the pathogenesis of ADOA may result from haploinsufficiency, with most of the OPA1 mutations causing loss of function of the mutant allele [7, 9]. Recently, the authors reported that OPA1 mutations spanning the GTP-binding pocket disorganize the mitochondrial pathway by abolishing GTPase activity or affecting the self-assembly of OPA1 proteins. These mechanisms could impair the energy supply in the highly energy-demanding compartments, LETTER TO THE EDITORS

Lack of association between estrogen receptor 1 gene polymorphisms and multiple sclerosis in southern Italy in humans.

Estrogen receptor 1 gene polymorphisms (ESR1) have been found to be associated with multiple sclerosis (MS) in both Japanese and Finnish populations. We investigated the association between ESR1 polymorphisms (PvuII and XbaI) and MS in a study of 132 MS patients and 129 controls from the same geographic background (southern Italy). Allelic and genotypic frequencies were not different between MS patients and population controls for either the PvuII or XbaI polymorphism. This result suggests that the association between a given disease and a genomic characteristic must be confirmed by separate investigations in different populations.